cns chapter 6 - uni-muenchen.de cha synthesis of cocaine j. org. chem. 2000, 65, 4773 a typical...
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Chemical Neuroscience a course for synthetic chemists
Transporters and Pumps
6
How to get polar compounds and ions across membranes
ion channels
ionophores
transporters / pumps
passive transport
active transport
Ionophores shuttle ions across membranes
Valinomycin is a potassium ionophore
OHN
O O
HN OO
O
O
HN
O
OO
NH
OO
O NHO
ONH
O
O
K+
OMe
Me
Me
D-Hyiv
L-Lac
L-Val
D-Hyiv
L-Lac
L-ValD-Hyiv
L-Lac
L-Val
D-Val
D-Val
D-Val
Merrifield synthesis: J. Am. Chem. Soc. 1969, 91, 2691
Monensin is a sodium ionophore
Kishi synthesis: J. Am. Chem. Soc. 1979, 101, 262
Still synthesis: J. Am. Chem. Soc. 1980, 202, 2120
OO
O
O OCOOMe
OMe
OHOH
Me
Me Me
MeH
MeOH
H
H
H
H
Na+
Me
Calcimycin (A-23187) is a calcium ionophore
Boeckmann synthesis: J. Am. Chem. Soc. 1991, 113, 5337
O
O
NO
NHMe
COO
O HN
Me
Ca2+
Proton ionophores (uncouplers)
They can be used to uncouple respiration from ATP-production in mitochondria.
HN
N
N
CCCP
HN
N
N
FCCP
O
OHNO2
NO2
DNP
F
F F N N
NON
HNNH
F F
BAM15
Cl
Ion channels, ionophores and transporters
Ion channels and ionophores pass ions along their electrochemical gradients.
Primary transporters hydrolyze ATP or use light energy to transport a solute against its (electro)chemical gradient.
Secondary transporters discharge chemical established gradients to transport a solute against its (electro)chemical gradient
Antiporters transport in opposite directions
Symporters transport in the same directions
The synapse
The synapse
http://en.wikipedia.org/wiki/Synapse
synaptic vesicle
transporter
vesiculartransporter
Neurotransmitter transporters
EAAT 1-5 (excitatory amino acid transporters)VGLUT 1-3 (vesicular glutamate transporters)
VAChT (vesicular acetylcholine transporters)
GlyT1,2 (glycine transporters)
GAT (GABA transporters)VGAT (vesicular GABA transporters)
DAT (dopamine transporters)NET (norepinephrine transporters)SERT (serotonine transporters)VMAT1,2 (vesicular monoamine transporters)
various peptide transporters
Cocaine has central effects
Until 1903 Coca Cola contained ca. 250 mg cocaine per liter (0.7 mM)
cocaine
NCOOMe
O
O
Na+
NH2HO
HO
dopamine
NHnortryptiline
pdb: 4M48
Na+
Cocaine inhibits the dopamine transporter (DAT)
NO
O
O OMe
NOH
O OH
(–)-cocaine ecgonine
N
O
tropinone
N
ψ-tropine
OHN
tropine
OH
N
(–)-hyoscyamineracemate: atropin
O
O
OH N
hyoscine = scopolamine
O
O
OHO
NCOOMe
O
O
O
ON
COOMe
α-truxilline
N
tropane(not a NP)
Tropane and Coca alkaloids
NO
O
O OMe
NOH
O OH
(–)-cocaine ecgonine
N
O
tropinone
N
ψ-tropine
OHN
tropine
OH
N
(–)-hyoscyamineracemate: atropin
O
O
OH N
hyoscine = scopolamine
O
O
OHO
NCOOMe
O
O
O
ON
COOMe
α-truxilline
N
tropane(not a NP)
Aspects of cocaine
NCOOMe
OBz
NO
O
O OMe
N
COOMe
OBz NMeOOC
OBz
NCOOMe
OBz
NCOOMe
OBz
NO
O
O OMe
methyl ester
NO
O
O OMe
benzoate
NO
O
O OMe
N-methyl group
NO
O
O OMe
NO
O
O OMe
NO
O
O OMe
NO
O
O OMe
NO
O
O OMe
tertary amine pyrrolidine piperidine
aldol 1,3-N,O
NO
O
O OMe
1,3-N,OMannich-retron
NO
O
O OMe
cocaine
NO
O
O OMe
tropane
N
O
tropinone
Molecular analysis of cocaine
Richard Willstätter
1915 Nobel Prize in Chemistry
Some Willstätter molecules
O
OH
HO
OH
OHCl
pelargonidin
O
OH
HO
OH
OHCl
cyanidin
OHO
OH
HO
OH
OHCl
delphinidin
OH
OH
N
Me
N
N NMg
OO
Me
Me
OOOMe
chlorophyll a
cocaine
NCOOMe
O
O
NCOOH
OH
ecgonin
N
O
OH
hyoscyamine (antagonist)
O
cyclooctatetraene cyclobutadiene(never made)
N
tropinone
O
The Hofmann degradation of cocaine
NHOOC
COOMe
OBz
This sequence established that cocaine contains a seven-membered carbocycle.
Chem. Ber. 1900, 33, 4011
1 1) HCl double ester hydrolysis → elimination
cocaine
NCOOMe
OBz
NCOOH
22) MeI N-methylation
NCOOHI
33) AgOH, Δ twofold Hofmann elimination of dimethylamine
HOOC
NCOOMe
OBz
HOOC
4 4) Pt, H2 hydrogenation
HOOC
5 5) NaN3, H2SO4 Schmidt rearrangement
H2N
6,7 6) MeI7) AgOH, Δ
methylation,Hofmann elimination
The Willstätter synthesis of tropinone
N
O Me2N
O
A heroic effort and one of the first total syntheses of a natural product. Inspired and enabled by degradation studies (via Hofmann eliminations). The overall yield was poor but the correlation was made.
Chem. Ber. 1900, 33, 4011
1,2
3,4
6-8
1) NH2OH2) Na/EtOH
3) MeI4) Ag2O/H2O
oxime formation,reduction
exhaustive methylation,Hoffmann elimination
methylation,Hofmann elimination
5 5) Br26) Me2NH
bromination,substutution and elimination
7) MeI8) Ag2O/H2O
O
NH2
NMe2
Cycloheptanone was available viaClaisen condensation/decarboxylation.
9 9) Br2, quinoline 1,4 dibromination, double elimination
Br
10 10) HBr hydrobromination
11,12 11) Me2NH12) Na/EtOH
aminationreduction of the diene
Me2N
13 13) Br2 → Δ key step: bromination followed by intramolecularnucleophilic substitution to form the nitrogen bridge
NBr
Br The tropane skeleton is in place.
NBr
Br
14-1614) NaOH15) Cl–16) 130 °C
elimination,chloride salt formation,monodemethylation
17,18 17) HBr18) H2SO4
hydrobrominationnucleophilic substitution under Sn1 conditions
19 19) CrO3 oxidation
N
O
tropinone
N
O≡
ϕ-tropine
tropidine
N
BrBr≡
N
N
OH
The Willstätter synthesis of racemic cocaine
Chem. Ber. 1901, 34, 1457
One of the first total syntheses (“vollständige Synthese”) of a complex natural product. A landmark achievement in natural product chemistry.
NO
COOMe
O
N
O
tropinone
N
O
1) 1) Na, CO2
N
O
2) 2) Na, HCl, H2O
NOH
COOH
(±)-ecgonine
+ isomers
formation of the sodium enolate,carboxylation
dissolved metal reduction via:
COONa
NO
COO
NOH
COOMe
4) 4) Bz2O benzoylation
NO
COOMe
O
(±)-cocaine
NOH
COOH
(±)-ecgonine
3) 3) HCl, MeOH Fischer esterification
Liebigs Ann. Chem. 1901, 317, 3163
The 1901 Willstätter synthesis of racemic cocaine
Chem. Ber. 1901, 34, 1457
N
O
OH
atropine (antagonist, racemate)
O
N
O
atropamine
O
N
O
belladonnine
O
N
O
O
Ph
(±)-cocaine
NCOOMe
OBz
Robert Robinson
1947 Nobel Prize in Chemistry
Robinson’s stroke of geniusJ. Chem. Soc. Trans. 1917, 111, 762
N
O
tropinoneOH
HNH2
O
OO
N OHOH
"imaginaryhydrolysis"
Robinson’s synthesis (and Schöpf’s improvement)
N
O
tropinone
H2O
low yield
NH2
O
OO
NH2
O
OO
N
O
tropinone
H2O
HOOC
COOH + 2 CO2pH > 7
42%
NH2
O
OO
N
O
tropinone
H2O
HOOC
COOH + 2 CO2pH 7 buffer
90%
Schöpf 1937:
O
H
O
H
H2N- H2O N
H
O
H
N
O–
COOHO
COOH N
O
COOH
HO
O OH
H
N
O
tropinone
N
OH
COOH
O OH
N
O
COOH
O O H
– 2 CO2H+
– H2O
A plausible mechanism
The Casale synthesis of cocaine
Forensic Sci. Int. 1987, 33, 275
N
cocaine
NH2
O
OO
COOMe
HOOC
COOMe
OBzN
COOMe
O
A “practical” synthesis that is in essence a variant of the Robinson tropinone synthesis. A similar synthesis was realized by Willstätter in 1923.
1
2
3
4
1) HOAc, Ac2O → MeOH
2) MeNH2,
3) Na-Hg, H2SO4
4) BzCl, py
formation of a cyclic anhydride → methanolysis via:
key step: Mannich condensation and decarboxylation via:
esterification
reduction of ketone to equatorial 3-hydroxy groupvia the more stable radical anion:
NO
O
O OMe
HOOC COOHO
HOOC COOMeO
N
O
OOMe N
OH
O OMe
NOH
O OMe
cocaine
N
O
OOH
O OMe
OHC CHO
O
O
O O
NO
COOMe
N
(+)-cocaine
OBzNE+
O
N
O
HH
tropinone
COOMe
The Cha synthesis of cocaineJ. Org. Chem. 2000, 65, 4773
A typical “concept-oriented synthesis”, wherein an enantiotopos-selective deprotonation is used. A synthetic equivalent for a C1 electrophile is employed. Probably for regulatory reasons, the unnatural enantiomer is made. The conversion of tropinone into racemic cocaine had been previously explored by Willstätter.
NLi
CH3 CH3
"chiral LDA"
NO
NN
O
O
NN
O
OHOH
PPh3
PPh3
O
O
OHOH
N N
O– –O
pybox
box
binol binap
taddol salen Zr ClCl
EBTHI
Homotopicityusually associated with C2-symmetry
HOOC COOH
HO OH
OAc
OAc
OAcMe
OAcMe
OO
Me
Me
O
H H
O
OMe
O
Me
OO
H
H
Me
Me
O
HH
O
OMe
MeO
H
H
NLi
CH3 CH3
HNN
N
Champix®
nonactin
O
O
H
H
O
OO
OHOHO
HOOC COOH
OH
OH
Enantiotopicityusually associated with Cs-symmetry (but sometimes applies to centrosymmetric molecules)
Diastereotopicityusually associated with C1
O OHO
O
NH2HO
AcNNAc
OTBS
O
O
O
O
1
2
3, 4
1) ,
2) TIPSOTf, lutidine
3) Li / NH34) BzCl, Et3N
key step: enantiotopos-selective deprotonation→ diastereoselective aldol addition, e.r. = 95:5
protection (needed for differentiation)
reduction,benzoylation
Tropinone is readily available via Robinson-Schoepf synthesis.
N
O
N
OTBSOH
O
N
OTBSOTIPS
O
N
OTBSOTIPS
OBz
→N
OLichiral lithium enolate
NLi
MeMe
H
OOTBS
stereoselective reduction via the more stable radical anion:
NO
R
NO OMe
OBz
5, 6
7
5) HF6) RuCl3 /NaIO4
methylation
diol deprotaction, diol cleavage
NO OH
OBz
NO OMe
OBz
(+)-cocaine
7) TMSCHN2
N
OTBSOTIPS
OBz
The Pearson synthesis of cocaine
Org. Lett. 2004, 6, 3305
N
(+)-cocaine
OBzN
meso-dialdehyde
COOMeO
H
O HNO≡
H
O
H
NO
H
O
H
A methodology- and concept-oriented synthesis. Pearson’s proprietary pyrrole synthesis is used and an organocatalytic aldol-desymmetrization of a meso-dialdehyde serves as a key step.
Me
O
O
analogous:
Wieland-Miescher ketone71% ee
O
O
O
O
O ONH
COOH
Me
O
OMe
O
O
OH
TsOH
PhH
DMF
NO
OH
O
O
3 mol%
Michael
enantiotopos -
differentiating !
93% ee
‡
Houk-TS
Hajos-Parrish-Eder-Sauer-Wiechert ketone
Proline-catalyzed asymmetric aldol reactionsReview: B. List, Tetrahedron 2002, 58, 5573.
NCOOMe
OBz1-3
4
5
6-8
1) LDA, Bu3SnH2) phthalimide, PPh3, DEAD3) H2NNH2, EtOH
4) 4 Å MS,
5) n-BuLi,
6) Boc2O7) Li, NH3/THF
8) TPAP, NMO
stannylation,Mitsunobu reaction,hydrazinolysis
condensation
key step: 2-azaallyllithium [3+2] cycloaddition to phenyl vinyl sulfide gives the desired 2,5-substituted cis-pyrrolidine
Boc protection,reductive removal of thiophenyl group and both benzyl ethers,twofold Ley oxidation
BnO CHO
BnO
SnBu3
NH2
BnO
SnBu3
N OBn
HN
SPh
BnO OBn
BnO CHO
SPh
2-azaallyllithium [3+2] cycloadditions provide the cis-2,5-disubstituted pyrrolidines whereas (2-aza-allyl)stannanes lead predominantly to the trans-2,5-disubstituted pyrrolidines.
NBoc
O
H
O
H
9
10, 11
9) L-proline, PhCH3
10) NaClO211) CH2N2
key step: intramolecular enol-exo-proline-catalyzed aldol reaction gives an unseparable 1:1 mixture of epimers
Pinnick oxidation,esterification
12 benzoylation under Steglich conditions
13, 14 deprotection,reductive amination
12) (Bz)2O, DMAP
13) TFA14) HCHO, NaBH3CN
NBoc
N CHOOH
Boc
N COOMeOH
Boc
N COOMeOBz
(+)-cocaine
meso-dialdehydeO
H
O
H
N COOMeOBz
Boc
The Tufariello synthesis of cocaineJACS 1979, 101, 2435
N
cocaine
COOMe
OBzNO COOMe
NCOOMeO
NMeOOC
O
≡
A methodology-oriented synthesis. A nitrone 1,3-dipolar cycloaddition is employed twice, establishing the 1,3-N,O-motif. The nitrone in itself is transiently protected as a cycloadduct. The reversibility of nitrone-cycloadditions was previously established by Edda Gössinger (University of Vienna).
NCOOMe
OBz
1
2
3
1)
2) m-CPBA
3)
oxidation and elimination to regioselectivelygenerate a second nitrone, possibly via:
1,3-dipolar cycloaddition
key step: 1,3-dipolar cycloaddition
NO
NO
MeOOC
NO
NO
MeOOC
O
The niitrone was made through HgO oxidationof pyrrolidine.
H
MeOOCOH
H
COOMe
COOMe
NO
COOMe
HMeOOC
OH
NCOOMe
OBz
4, 5
6
7
4) MsCl5) DBN
6) 144 oC
7) MeI
key step: nitrone is deprotected via a retro-1,3-dipolar cycloaddition, which triggers an intramolecular 1,3-dipolar cycloaddition via:
mesylation,dehydration
N-methylation
NO
COOMe
NCOOMeO
NO COOMe
I
NMeOOC
O
HMeOOC
OH
N
NDBN =
≡
NO
COOMe
HMeOOC
NO COOMe
8 reductive N-O bond cleavage
9 benzoyl ester formation
8) Zn, AcOH
9) BzCl, NaOH
(±)-cocaine
NCOOMe
OBz
NCOOMe
OH
I NO COOMe
How is cocaine really produced ?
Annual production: ca 1000 tons; 2008 sales: ca. $ 77 billion the US alone ! For comparison: the 2006 sales of Lipitor (best-selling medicinal drug) were $ 14.4 billion.
N
N-methylΔ1-pyrrolidinium
ion
HNHOOC
NH2
NH
NH2
arginine
O
CoA-S2
N
OO
CoA-S NCOOMe
OBz→ [O]
The biosynthesis of cocaine
NCOOMe
OBzCoAS
OHOOC COOH
NH2SAM
SCoA
OSCoA
OSAM
NCOOMe
OBz
plants
1) ornithine decarboxylase, PLP decarboxylation with pyridoxal phosphate (PLP)
HOOC COOH
NH2
L-glutamic acid
H2N COOH
NH2
L-ornithine
1
H2N
NH2
putrescine
2) SAM, putrescine N-methyltrans- ferase
N-methylation2
HN
NH2
N-methylputrescine
NCOOMe
OBz
HN
NH2
N-methylputrescine
3) methylputrescine oxidase diamine oxidation3
NH O
N
+ H2O- H2O iminium formation
4) acetyl-CoA intermolecular Mannich reaction via:4
N
O
SCoA
5) acetyl-CoA β-ketothioester formation5
N
O O
SCoA
N
O
SCoA
(±)-cocaine
NCOOMe
OBz
N
O O
SCoA
6) [O]6 oxidation to pyrrolinium cation → intramolecular Mannich reaction → thioester hydrolysis via:
NCOOH
O
N
O
HO SCoA
7) SAM8) NADPH
7,8 methyl ester formation,reduction
NCOOH
OH
9) benzoyl-CoA9 ester formation
L-Phe CoAS
O
methylecgonine
Amphetamines run DAT in reverse
O
Me
HN
HN
methamphetamine(Crystal Meth, Tina, Ice)
mephedrone
O
Me
NH2
cathinone(Khat)
O
Me
HN
methcathinone
NH2
amphetamine(Aderall)
Me
NH2
amphetamine(active enantiomer)
Me
HN
MDMA(Extasy)
O
O
Me
HN
methamphetamine(active enantiomer)
Me
HN
pseudoephedrin
OH
Me
HN
ephedrin
OH
Me
HN
fenetyllin (Captagon)
N
NN
NO
O
Smurfs, ammonia and “shake and bake”
Me
HN
pseudoephedrin
OHH2 or 2 e-, 2 H+
Me
HN
metamphetamin
O
H2N
CHO NO2
April 1945
Walter White’s chemistry
Convallaria majalis (Maiglöckchen, lily of the valley)
strophantidine glycosides target the Na+/K+-ATPase
ricin targets the ribosome
methamphetamine targets DAT
seeds from Ricinus communis (castor bean)
Homo sapiens ssp. Heisenbergensis (the deadliest of them all)
O
OHRO OH
H
H
Me
O
O H
Me
HN
methylphenidate (Ritalin)
HN
MeO OH
Ritalin inhibits DAT and NET
Ritalin prescriptions for adults are becoming a problem in the U.S.
Antidepressants
“Melencholia I” by Albrecht Dürer (1514)
Depression can affect highly accomplished people
Abraham Lincoln was known to take “blue mass”, a highly toxic medicine containing mercury, against his depressions.
Ludwig Boltzmann killed himself in 1906probably due to depression and certainlynot because his work was ignored.
SERT is a major target for antidepressants
Many of these drugs are selective serotonin reuptake inhibitors (SSRIs).
ClCl
NHMe
sertraline (Zoloft)
NH
O
F3C
fluoxetine (Prozac)
N
N
imipramin (Tofranil)
ON
F
NC
escitalopram (Cipralex)
OH
N
OMe
venlafaxine (Effexor)
S
NH
O
duloxetine (Cymbalta)
O
Me
HNCl
bupropion (Welbutrin)
NH
F
O
paroxertin (Paxil)
O
O
A model of escitalopram bound to SERT
ON
F
NC
seen obliquely from the extracellular side
Mesembrine inhibits SERT
“Kanna" is prepared by fermenting Sceletium tortuosum and has been used, initially in South Africa, to elevate mood and decrease anxiety, stress and tension.
Sceletium tortuosum
N
OMeOMe
OH
mesembrine
The Stevens synthesis of mesembrine
A classic exercise in Mannich chemistry that also features an interesting ring expansion.
MeO
MeO
NMe
OMeOMe
HO
MeNH2
CN
O Cl Cl
J. Am. Chem. Soc. 1968, 90, 5580J. Org. Chem. 1975, 40, 3495
1-3 1) LDA,2) DIBAL-H3) MeNH2
cyclopropane formation by double alkylation,nitrile reduction,imine formation
4 4) NH4I key step: rearrangement via:
5 5) HCl, key step: Robinson-type annulation
OMeOMe
NC
Cl Cl
OMeOMe
NMe
NMe Ar
I-
HNMe Ar
H
I
OMeOMe
NO
NMe
OMeOMe
HO
Me
mesembrine
The Keck synthesis of mesembrine
An unusual synthesis featuring a nitroso-ene reaction.
J. Org. Chem. 1982, 47, 1302
MeO
MeO
Br
NMe
OMeOMe
HO
OMe
O
MeI
Ac2O
NH2OH
NMe
OMeOMe
HO
1 1) → H3O+ nucleophilic attack on the vinylogous ester→ β-elimination of water
2,3 2) NaBH43) Ac2O, py
enone reduction,acetylation
4 4) LiHMDS, TBSCl → Δ key step: Ireland-Claisen rearrangement
OMe
O Li OMe
OMe
O
OMe
OMe
OAc
OMe
OMe
OHO
OMe
OMe
5 5) SOCl2, DMF → NH2OH hydroxamic acid formation via the acid chloride
6 6) Pr4NIO4, 9,10-dimethylanthracene
key step: nitroso-Diels-Alder reaction
OHO
OMe
OMe
NHO
OMe
OMe
OH
NO
OAr
Ar =
OMeOMe
NMe
OMeOMe
HO
NO
OAr
7 7) PhMe, Δ key step: retro-Diels-Alder reaction →nitroso-ene reaction
NOH
O
OMeOMe
H
8-10 8) TiCl39) NaH, MeI10) NBS, H2O
N-O bond cleavage,N-methylation,bromohydrin formation
NMe
O
OMeOMe
HHOBr
NMe
OMeOMe
HO
NMe
O
OMeOMe
HHOBr
11,12 11) Bu3SnH, AIBN12) PCC
radical dehalogenation,oxidation
NMe
O
OMeOMe
HO
13-15 13) (CH2OH)2, p-TsOH14) LiAlH415) HCl
ketal formation,lactam reduction,ketal deprotection
NMe
OMeOMe
HO
mesembrine
The Zhang synthesis of mesembrine
A very effective, asymmetric synthesis hat hinges on a transition metal catalyzed allylation and arylation.
MeO
MeO
Br
NMe
OMeOMe
HO
MeNH2
OAcOEt
O
Org. Lett. 2009, 11, 555
NMe
OMeOMe
HO
1 1) Pd(OAc)2, BINAP, NaHMDS,
ArBr → NaHMDS,
key step: sequential α-arylation and allylation
2 2) OsO4, NaIO4 alkene dihydroxylation and cleavage
OEt
O
OAc
OMeOMe
BrArBr =
OEt
O
OMe
OMe
OEt
O
OMe
OMe
O
5 5) Li, NH3 Birch reduction
NMe
OMeOMe
HO
mesembrine
3,4 3) MsCl, THF/H2O4) MeNH2 → NaBH3CN
enol ether cleavage,reductive amination
OEt
O
NMe
OMeOMe
O
OMe
OMeO
Reserpine inhibits VMAT
Due to side effects, reserpine has been discontinued as a clinically used antidepressant.
NH
N
OMeMeOOC
H
H
reserpine
MeO
O
O
OMeOMe
OMe
H
Rauwolfia serpentinata
The Woodward synthesis of reserpine
A celebrated “classic” featuring an early applications of the Diels-Alder reaction in natural product synthesis. One of Woodward’s signature achievements, it makes extensive use of reactions that occur selectively from the convex side of polycyclic systems.
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
O
O
COOMe
Cl
O
OMeOMe
OMeNaOMeCH2N2
NHMeO
NH2
J. Am. Chem. Soc. 1956, 78, 2023J. Am. Chem. Soc. 1956, 78, 2657
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
1
2,3
1) endo Diels-Alder reaction
diastereoselective double Meerwein-Ponndorf-Verley reduction → lactonization,intramolecular bromoetherification
2) Al(Oi-Pr)3, i-PrOH
3) Br2
O
O
COOMe
O
O
H
H COOMe
O
H
4 elimination → Michael addition from the convex face4) NaOMe, MeOH
OO
BrH HH
The two double bonds and carbonyls are nowdifferentiated and can be elaborated separately.
O
H
OO
OMeH HH
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
5,6 bromohydrin formation by bromination from theconvex face,oxidation
5) NBS, H2SO4, H2O
6) H2Cr2O7, AcOH
O
H
OO
OMeH H
Br
O
7 key step: double reductive elimination via:7) Zn, AcOH
O
H
OO
OMeH H
Br
OO
H
OMeH
Br
O
ZnO
H
COOOMeH
BrZn
O
H+
OHH
COOHOMeHO
COO
OHH
COOHOMeHO
O
H
OO
OMeH HH
H
Zn
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
OHH
COOHOMeHO
8-10 methyl ester formation,acetylation,dihydroxylation from the convex face
8) CH2N29) Ac2O10) OsO4, NaClO3
OAcH
COOMeOMeHO
HOHO
11,12 key step: double diol cleavage,methyl ester formation
11) HIO412) CH2N2
H
HO
HOHO HIO4 H2O
H
H
OHO
HOHO
HO
HIO4
– HCO2H
CH2N2
MeOOC
OAc
COOMeOMe
O
H
CHO
COOMe
AcOMeOOC
MeO
H
HO
OO
H
H
O
HO
O
H
H
O
MeO
O
≡
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
MeOOC
OAc
COOMeOMe
O
H
13 key step: imine formation with methoxytryptamine→ reduction and condensation to yield the lactam
13) → NaBH4
NHMeO
NH2
OAc
H
MeOOCOMe
H
NOHN
MeO
14key step: Bischler-Napieralski reaction followed by reduction.14) POCl3 → NaBH4
OAc
H
MeOOCOMe
H
NNH
MeO
H NClHN
MeO
NHN
MeO
H
The undesired isomer was formed due to hydride delivery from the α-side.
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
OAc
OAc
H
MeOOCOMe
H
NNH
MeO
H
≡
MeO E
15,16 methyl ester and acetate hydrolysis,lactone formation
15) KOH, MeOH16) DCC, py
The minor, less favorable conformer is trapped and"clamped" in a conformation that will allow theepimerization of the crucial stereocenter.
E = COOMe
N
HN
OMe
OMeO
N
HN
OMe
O
O
H
MeOOCOMe
H
NNH
MeO
HO
OMe
OMeOMe
17
key step: epimerization via a planar intermediate:
17) PivOH, Δ
OMeO
N
O
18 lactone hydrolysis18) NaOMe, MeOH
NH
N
H
H+
NH
N
H
H
NH
N
NH
N
H
H
-H+NH
N
H
H+H
NH
MeO NH
H
OMe
MeO
O
HOH
OMeO
N
HN
OMe
O
HN
OMe
MeO
MeOOMe
O
Cl19 ester formation19) py,
reserpine
NH
MeO NH
H
OMe
MeO
O
HO
OMe
OOMe
OMe
NH
MeO NH
H
OMe
MeO
O
HOH
The Jacobsen synthesis of (+)-reserpine
Sixty years after Woodward an enantioselective synthesis that features two of Jacobsen’s signature reactions: a kinetic hydrolytic resolution and a thiourea-mediated (formal) aza Diels-Alder reaction.
Org. Lett. 2013, 15, 706
OMe
OMeOMe
Cl
O
TBSOO
TMSCHN2 H OEt
O
Br TMS
N
O
OMe
MeI
NH
NH2
MeO
NH
H
OMe
MeO
O
HO
OMe
OOMe
OMe
NH
MeO
NTs
MeO NH
H
OMe
MeO
O
HO
OMe
OOMe
OMe
1 1) BnOH (0.45 eq), Co(salen)OTf key step: Jacobsen hydrolytic kinetic resolution
5,6 5) Ti(Oi-Pr)3Cl,6) TfOH,
diastereoselective allylation,alcohol protection with a Bundle-type reagent
TBSOO
TBSO
OHOBn
2-4 2) NaH, MeI3) Pd-C, H24) (COCl)2, DMSO, Et3N
methylation,benzyl deprotection,Swern oxidation
TBSO
OMe
O
Br TMS
PMBO CCl3
NH
7 7) t-BuLi, Weinreb ketone synthesisN
O
fragment A
OMe
TBSO
OMe
PMBO
O
TBSO
OMe
PMBO
Br
NTs
MeO NH
H
OMe
MeO
O
HO
OMe
OOMe
OMe
8-10 1) HCOOEt, Et3N2) POCl33) TsF, Cs2CO3
amide formation,Bischler-Napieralski reaction,tosylation
11 11) thiourea, fragment A, AcOH key step: organocatalyzed formal aza-Diels-Alder
NH
NH2
NTs
N
MeO
MeO
Ph N NH
NHPh O
t-Bu S
NH2
thiourea
NH
H
OPMBOMe
TBSO O
N
RNthiourea
HMannich
NH
Michael
N thioureaR
N
O→ H2O
fragment A
TBSO
OMe
PMBO
O
NTs
MeO
NTs
MeO NH
H
OMe
MeO
O
HO
OMe
OOMe
OMe
12-14 12) HF•py13) DMP14) piperidine, p-TsOH
deprotection,Dess-Martin oxidation,aldol reaction
NH
H
OPMBOMe
HO
15,16 15) NaClO2, NaH2PO416) TMSCHN2
Pinnick oxidation,esterification
HO
NH
H
OPMBOMe
TBSO O
NTs
MeO
NTs
MeO
NH
H
OPMBOMe
MeOO
HO
NTs
MeO
17-19 17) n-BuLi, TFAA18) DBU, Δ19) Crabtree catalyst, H2
alcohol trifluoroacetylation,elimination,hydrogenation
NH
H
OPMBOMe
MeO
O
H
20-22 20) TfOH, 1,3-dimethoxybenzene21) Na-Hg, NaH2PO422)
PMB deprotection,tosyl deprotection,acylation
NH
H
OMe
MeO
O
H
OMe
OMeOMe
Cl
O
O
OMe
OOMe
OMe(+)-reserpine
NH
H
OPMBOMe
MeOO
HO
NTs
MeO
NTs
MeO
NTs
MeO
3 Na+
2 K+
pdb 4YHT
extracellular
intracellular
The Na+/K+-ATPase establishes ionic gradients
extracellular
intracellular
Ouabain inhibits the Na+/K+-ATPase O
OH
HO
O OH
HO
H
H
OH Me
O
O
Me
OHHO
HO
ouabain
pdb 4YHT
Cardiac glycosides (cardenolides)
O
OH
HO
O OH
HO
H
H
OH Me
O
O
Me
OHHO
HO
ouabain
O
OH
HO
HO OH
HO
H
H
OH Me
O
ouabagenin
OO
HO
HO
OHOHO
HOH
O
Me
OHO H
H
H
Me
O
O
digitoxin
HO
OO
OO
OHMe
OHHO
H
H
OHMeMe
O
Me
OHRO H
H
H
Me
O
cardenolide core
≡
Science 2013, 339, 59-63
An elegant semisynthesis starting from a (now) widely available steroid.
The Baran synthesis of ouabagenin
MeHO
H
HHO
OH
HO
HOOH
OO
MeO
H
H
HO
HO
O
OO
O
cortisone acetateO
OOAcOHMeO
Me
H
H
H
MeHO
H
HHO
OH
HO
HOOH
OO
1
2, 3
1) NaBH4 → NaIO4
2) p-TsOH, ethylene glycol3) hν (450 W), SDS solution
cortisone acetate
adrenosterone
ketone protection,key step: Norrish-Yang reaction (type II)
ketone reduction → diol cleavage
MeHO
H
H
HO
O
OO
O
OOAcOHMeO
Me
H
H
H
O
OMeOMe
H
H
H
MeHO
H
HHO
OH
HO
HOOH
OO
6-8
4, 5 4) hν (90 W), NIS, Li2CO3
5) TiCl4 → AgOAc
key step: cyclobutanol fragmentation and iodination,selective deketalization → iodide hydrolysis
6) H2O2, NaOH7) SeO28) H2O2, NaOH
directed epoxidation,dehydrogenation,directed epoxidation
MeHO
H
H
HO
O
OO
MeO
H
H
HO
HO OO
MeO
H
H
HO
HO
O
OO
O
MeHO
H
HHO
OH
HO
HOOH
OO
12-14 reduction under Birch conditions,selective deprotectionSaegusa oxidation,olefin isomerization
11) Li, NH312) PPTS, acetone13) TMSOTf, Et3N; Pd(OAc)214) SiO2, DIPEA, perfluorotoluene
9-11 9) Al-Hg, NaHCO3 (sat.)10) PPTS, acetone11) LiEt3BH
key step: reductive opening of epoxides,diol protection,ketone reduction and boronic ester formation
MeO
H
H
HO
HO
O
OO
O
MeO
H
H
H
O
O
O
O BEt
OO
MeHO
H
HO
O
O
O BEt
O
ouabagenin
15) Co(acac)2, PhSiH3, O216) N2H4, Et3N; I2, Et3N17) Bu3SnX, Pd(PPh3)4, CuTC
18) CoCl2•6H2O, NaBH419) Barton’s base 20) HCl (conc.)
2-tert-Butyl-1,1,3,3,-tetramethylguanidine (Barton’s base)
N N
N
Bu3Sn
OO
Bu3SnX =
15-17
18-20
Mukaiyama hydration,Barton vinyl iodide synthesisStille cross coupling
reduction, olefin isomerization,deprotection
MeHO
H
HO
O
O
O BEt
O
MeHO
H
HO
O
O
O BEt
OH
OO
MeHO
H
HHO
OH
HO
HOOH
OO
SCOOCu
CuTC
Palytoxin also inhibits the Na+/K+-ATPase
HO NH
NH
O O
OH
Me OH
OHO
HO OHOH
HO
HOH
HO OH
OHOHMeOOMe
Me
O
HO
OHOHHO
OH
OH
Me
OH
OHO
OH
HO
H
OH
OH
O
OH
OHOH
OH
HO
OHOH
O
OO
O
OHH2N
OH
OH
HOOH
OH
HOHO
OHMe
OH
palytoxin
Kishi synthesis: J. Am. Chem. Soc. 1994, 116, 11205